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Diabetes: a rising tide.
Christopher Whitty
Gresham College 2017.
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Diabetes has been described since Egyptian texts in 1552 BC (Hesy-Ra).
• Others noticed ants attracted to the urine of sufferers.
• ‘The melting of flesh into urine’ (Arateus, 150 AD).
• Early diagnosis involved tasting urine.
• Link with exercise and diet was made early.
Constantine the African examines urine.
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A recognition there were two types of patients with diabetes.
• From around the 1770s there was a recognition there were at least two types of diabetic patients.
• One group often died within weeks. This is what we would call Type 1 diabetes.
• For the second, survival was much longer and diet might help. This is what we call Type 2 diabetes. Annual sugar consumption in
the UK and USA, and obesity in USA. Johnston RJ 2007.
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Important scientific milestones: the pancreas.
• In 1869 Paul Langerhans, a doctoral student, describes clusters of clear cells in the pancreas. ‘Islets of Langerhans’.
• 1889 von Mering and Minkowski show that removing the pancreas from dogs causes diabetes.
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The breakthrough was the isolation of insulin, and giving it to patients.
• The Canadian team of Banting, Best, MacLeod and Collip extracted and purified insulin.
• Given to Leonard Thompson, aged 14, in 1922, drifting in an out of coma. Thompson went on to live another 13 years.
• Banting and MacLeod were awarded the Nobel Prize.
Leonard Thompson
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Diabetes is common.
• An estimated 4.3 million people in the UK living with diabetes.
• Around 3.5m diagnosed.
• Around 415m globally.
• In all walks of life.
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Diabetes has risen since 1990 as a proportion of morbidity. Global Burden of Disease study 2017
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Physiology of diabetes and glucose control..
• …. is complicated.
• But the essence of it is simple.
• The body needs to keep glucose in a narrow range. Either too much or too little is a problem.
• The pancreas ß cells produces insulin in response to high glucose.
• Other cells respond to this by storing energy.
Cryer PE et al 2006
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Type 1 diabetes- around 10%
• The pancreas Islets of Langerhans produce insulin from ß cells.
• These die off- an autoimmune disease.
• Without insulin the body cannot regulate glucose and energy.
• Eventually there is almost no insulin.
• The body usually responds to insulin normally. Shutterstock
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Type 2 diabetes.
• The pancreas produces insulin in response to glucose.
• The body responds abnormally to this insulin, not reducing glucose as much as it should.
• Or too little insulin is produced.
• The effect is glucose goes up.
Shutterstock
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Age structure of Type 1 and Type 2 diabetes are very different. UK National Diabetes Audit 2017
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Gestational diabetes.
• Around 5% of pregnancies.
• Occurs in 2nd or 3rd trimesters.
• Usually resolves after child born.
• But 7x increased risk of subsequently developing Type 2 diabetes.
• Pregestational diabetes rising in pregnancy.
Pregestational diabetes. Coton et al 2016
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Genetic inheritance and diabetes.
• Type 1: 85% have no first degree relatives affected, but
• The risk is about 15x higher if you do.
• 2-3% risk with mother, 6-9% risk with father, 30% if both. 30-70% for identical twins.
• Type 2: clusters in families, but a complex relationship. 2-6x more likely if a family member has it.
Diabetes.co.uk
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Ethnicity and diabetes.
• Children of Asian origin around 8.9x more likely to have Type 2 diabetes than their White counterparts, children of African heritage were 5.8 times more likely.
• South Asian and African heritage 2-4x more likely to develop Type 2 diabetes. Middle East heritage also high risk.
• Also higher risk of gestational diabetes.
Diabetes UK
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Ethnic differences: prevalence of diabetes in London. Dreyer et al 2009.
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The major risk for Type 2 diabetes is being overweight.
• 80-85% of Type 2 diabetes is accounted for by people being overweight or obese.
• An increase with deprivation (cf Type 1).
• Where people with Type 2 diabetes lose weight diabetes may go away.
Diabetes.co.uk
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Trends in diabetes in the US over time. Most of the increase in those with BMI > 30. (Menke et al, JAMA 2015
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Prevalence of Type 2 diabetes rose very rapidly from the 1960s to 2010.
• Three possible drivers:
• Rising obesity.
• Changes in diagnosis and medical practice.
• Better survival.
• Data from 2009 Diabetes UK report.
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Obesity in the UK. Over 2 decades from 15%-26%. Broadly stable last few years.
Percentage obese (BMI>30) by year. Health Survey for England.
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Prevalence rates diabetes rising (R), but incidence probably stable or falling (L). Data for UK males. Zghebi S et al 2017
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Data from Scotland- slightly reducing incidence in men (a) and women (b) varying by deprivation group. Read S et al 2016
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A recent study of GP practice data. Similar findings in other industrialised countries. Zghebi S et al. 2017
• Annual mortality rates are falling for Type 2 diabetes.
• Prevalence rose from 3.2% to 5.3% from 2004-2014.
• Incidence around 44/10,000 PYR in 2004, to 37 in 2014.
• Mortality rates fell from 319/10,000 PYR to 216 over the same period.
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Untreated diabetes.
The symptoms of untreated diabetes include:
• Going to pass urine frequently, with thirst.
• Tiredness.
• Weight loss.
• Skin infections, thrush and delayed wound healing.
Diabetes Concept
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Diabetic ketoacidosis(DKA) and hyperosmolar states (HHS/HHNS). Medical emergencies.
• Usually in undiagnosed Type 1 diabetes, or when people have not taken their insulin.
• Blood glucose goes very high, ketones build up, blood becomes acidic.
• Eventually lapse into coma.
• In hyperosmolar hyperglycaemic state (HHS or HHNS) diabetics with either Type 2 or Type 1 have life-threateningly high glucose without ketones. Usually illness or infection triggers it.
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Insulin treatment.
• The first, and most important drug was insulin.
• The key to making a normal life possible was developing long-acting as well as short-acting insulin.
• Insulin can be given by injection, or pump.
• Beware hypoglycaemia. Diabetes.co.uk
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Insulin naturally varies during the day. Ideally artificial insulin mimics this.
Jakob Suckale, Michele Solimena
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Oral hypoglycaemic drugs operate by several mechanisms
Include:
• Stimulate insulin production from the pancreas directly (eg sulfonylureas, repaglinide).
• Decrease liver glucose production (eg metformin).
• Inhibit breakdown of gut enzymes GLP-1 and GIP which reduce glucose and stimulate the pancreas (eg DPP-4i).
Cryer
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Metformin.
• French lilac used in traditional medicine. Contains guanidine.
• Derivatives found to reduce sugar levels in rabbits.
• From this eventually biguanides- the most important is metformin. Used in diabetes from 1957.
Galega officinalis / French lilac / goats rue.
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Sulfonylureas.
• Discovered by chance by Marcel Janbon (1942) when testing sulfonylurea antibiotic against typhoid.
• Include drugs such as glibenclamide, gliclazide.
Dr. T Rao
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Dipeptidyl peptidase-4 inhibitors (DPP-4i).
• Several drugs in this class, more being developed.
• First, sitagliptin, was licenced in 2006.
• Work indirectly by preventing the breakdown of the gut enzyme incretins.
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For both Type 1 and Type 2 diabetes, without very good glucose control there are several major risks.
These include:
• Heart disease and heart attacks.
• Stroke.
• Eye disease and blindness.
• Skin infections, peripheral vascular disease and nerve damage leading to ulcers and limb loss.
• Kidney disease and renal failure.
• Serious infections.
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There has been a substantial reduction in complications from diabetes (US data). Gregg E et al NEJM 2014
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Diabetic retinopathy. Moderate (L) and severe.
Shutterstock
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Controlling blood sugar more effectively substantially reduces retinopathy.
Percentage with retinal change progressions. DCCT. NEJM, 1993.
And this is sustained for severe retinopathy (OR 69%). EDIC. NEJM 2000.
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The difficulty is the balancing act on control of blood sugar. Short term risk of hypos v long term gain.
DCCT group, NEJM, 1993
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Retinopathy treatment: laser therapy and anti-VEGF injections.
National Eye Institute Shutterstock
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Foot ulcers in diabetes. NHS Digital data.
• Around 60,000 people with diabetes have foot ulcers at any time in UK. Bad prognostic sign.
• Cost around £1Bn a year.
• Around 7000 amputations a year in UK. Only half survive >2 years.
Laborde M, Podiatry Today
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Good glycaemic control reduces amputations in Type 2 diabetes. Risk ratio 0.65 on meta-analysis.
Hasan R et al 2016
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Considerable variation across the country on amputations in diabetes.
Pathways may include:
• Delayed diagnosis of diabetes.
• Less good glycaemic control.
• Less good foot care.
• Delayed presentation with foot problems.
• Less effective non-invasive treatment.
• Local surgical practice. PHE data.
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Renal disease
• Diabetes is one of the leading causes of renal failure.
• Tight glucose control delays onset of kidney disease, but probably not progression.
• Controlling blood pressure, especially with an ACE inhibitor drugs delays onset.
Anna Frodesiak (with patient consent)
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Significantly increased risk of infections. Include skin, urinary tract, influenza complications.
Fu a et al 2014. Urinary tract infections in those with newly acquired diabetes.
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Cardiovascular disease mortality: heart disease and stroke. Type 1 (L) and Type 2. Rawshani et al 2017 NEJM; Swedish data.
36,869 patients, 42% reduction mortality
457,473 patients 46% reduction
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Heart disease advances.
There is no clear evidence that tight glycaemic (glucose) control significantly reduces cardiovascular disease. Reductions similar to non-diabetics including: • Smoking going down • Blood pressure control • Cholesterol lowering • ACE inhibitor drugs • ß-blockers • Aspirin • Exercise • Coronary stents
Banchory Group Practice
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By attention to detail and incremental scientific advance diabetes mortality is falling.
Type 1 diabetes- all cause mortality- 29% reduction.
Type 2 diabetes- 21% reduction over 15 years.
Rawshani et al 2017
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Gastric surgery (bariatric surgery).
• In people with severe obesity bariatric surgery leads to weight loss.
• If they have Type 2 diabetes this often resolves, and the reduction in blood sugar is maintained.
Schauer et al, NEJM 2017
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Prevalence of obesity age 18+ (female) WHO 2017.
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Prevalence of raised fasting blood glucose (age 18+, female). WHO 2016.
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Wealthy country trends and projections in obesity. OECD 2017
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Global overweight- children and adolescents. WHO 2017.
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We, the public, need to engage with the food industry on this. Pleasure, profits and health are not mutually incompatible. But it needs a different approach.
My local supermarket, last weekend.
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Don’t get all your diabetes advice from newspaper headlines… and they will often warn of dire consequences from state intervention.
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Ladder of state intervention.
• Ban.
• Tax heavily.
• Regulate.
• ‘Nudge’ tax or intervention.
• Mass voluntary programme.
• Engage with industry.
• Inform.
• Leave up to individuals.
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We will need multiple interventions, all with a modest but incremental impact.
We do not yet know the optimal mix.
Examples of possible state interventions include:
• Sugar tax on fizzy drinks
• Traffic light labelling of foods
• Restricting direct advertising to children
• Restricting fast food outlets near schools
Economist
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The aim should be not to reduce enjoyment, but to reduce unnecessary energy intake.
8.5g fat
0g fat
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New directions in science for treatment and prevention are occurring all the time.
Examples include:
• Islet cell transplants.
• Pancreatic transplant.
• Artificial pancreas.
• Immunotherapy in early Type 1 diabetes.
• Low calorie diets to put Type 2 diabetes into remission.
Diabetes UK